UTI is an exceedingly common outpatient problem among young healthy women, resulting in considerable morbidity and health care costs. Increasing antibiotic resistance, particularly among community-acquired UTIs, is making treatment of these infections even more problematic. Thus, novel, safe and effective non-antimicrobial prevention strategies are urgently needed. One approach that has been of interest to the public, health care providers, and the scientific community is ingestion of cranberry products for prevention and/or therapy of UTI. However, despite it's popularity, there have been no studies correlating in vitro effects of cranberry to clinical effects, making it difficult to explain mechanistically the outcomes observed in clinical trials. Thus, studies utilizing well-characterized cranberry products, assessing dose-range effects, and relating in vitro measures of activity to clinical outcome measures are needed as proof-of-principle that cranberry has biological activity and efficacy in the prevention of UTI. Performing these studies comprises the basis for the main aims of this proposal. Specific Aim 1 involves a Phase 1 study assessing urinary anti-adherence activity of urine collected from women pre and post ingestion of escalating doses of cranberry juice. This will be followed by a Phase II "proof-of-concept", placebo-controlled, randomized clinical trial of prevention of UTI in women with a history of recurrent UTI. The clinical study will assess the efficacy of low and high doses of cranberry juice and provide a correlation between the clinical outcomes and our in vitro measures of activity, namely inhibition of E. coli adherence to bladder epithelial cells and mannose-resistant hemagglutination. Assessment of vaginal E. coli colonization and virulence characteristics of E. coil strains causing UTI in the cranberry versus placebo treated women will further enhance our understanding of the breadth of activity of cranberry juice in terms of anatomic sites as well as bacterial species and microbial virulence characteristics. Given the increasing prevalence of antimicrobial resistance in E. coli strains causing UTI, and the absence of any effective means of prevention other than antimicrobials, demonstration of the feasibility and effectiveness of using cranberry juice would represent a major breakthrough in non-antimicrobial interventions for prevention of recurrent UTI in healthy reproductive-age women.